Olfaction is critical for survival, and in humans, diminished olfactory capacity as seen with aging, injury, or disease may compromise health and quality of life. Olfactory sensory neurons (OSNs) serve as the initial site of olfactory signaling, and thus they are critical for olfactory function. The development of OSNs is a complex process that must integrate neuronal proliferation, differentiation, and survival. While progress has been made on the mechanisms that mediate odor detection in OSNs, relatively little is know regarding the factors that are critical for their homeostasis. We demonstrated that cyclic GMP (cGMP) plays a role in the proliferation, differentiation, synapse formation, and neuroprotection of OSNs. cGMP is generated by soluble guanylyl cyclases (GCs) which are activated by the gaseous messengers NO (made by nitric oxide synthase (NOS)) and CO (made by heme oxygenase (HO)). cGMP is also produced by receptor GCs which are activated by extracellular ligands and Ca2+. Our overall hypothesis is that cGMP plays a role in regulating OSN proliferation, differentiation, and survival, and in the protection of OSNs from stress. The specific effect that cGMP has depends upon neuronal }status} (age and priming by other factors), and the mechanism, timing, and site of cGMP production. The goal of this proposal is to delineate the mechanisms that mediate these actions. We employ molecular and cell biological approaches using in vitro and in vivo models to investigate testable hypotheses. Aim 1 will utilize in vitro cultures, in vivo sensory stimulation and deprivation models, and biochemical and genetic approaches to investigate the regulation of the MEK/Erk and PI3K/Akt signaling pathways by cGMP to contribute to OSN survival. Aim 2 will use these models to study the role of cGMP in OSN differentiation and synaptogenesis. Aim 3 will utilize in vitro and in vivo models of sensory stimulation and deprivation, and biochemical and genetic approaches to study the role of cGMP in remediating the effects of stress on OSN survival. The rationale for these studies is that understanding the factors that regulate the survival of OSNs is essential for strategies aimed at preserving olfactory function. PUBLIC HEALTH RELEVANCE: The olfactory system is critical for survival, and in humans, diminished sensory capacity seen with aging, injury, or disease compromises health and quality of life. Olfactory sensory neurons (OSNs) serve as the initial site of olfactory signaling, and thus their survival is critical for olfactory function. Our studies have demonstrated that the second messenger cyclic GMP (cGMP) plays critical roles in the development and survival of OSNs, and in their response to stress. In this proposal, we study the mechanisms of these effects to evaluate the role that cGMP plays in the survival of these neurons. These findings have the potential to provide the basis for the development of therapeutic agent(s) to rescue neurons from death in response to injury.